Summary Pancreatic cancer holds the worst survival rate of the common malignancies, in part due to the poor response to treatments. The clinical options available to pancreatic cancer (PDA) patients are determined by the extent of disease progression, and unfortunately the vast majority of patients are ineligible for curative surgical approaches. African Americans and other underrepresented minorities have a higher incidence of, and mortality from, pancreatic cancer. In particular, African Americans have a relative risk of 1.7 for men and 1.5 for women. While Hispanic Americans do not exhibit the same level of elevated risk as African Americans, both populations are at higher risk for diabetes and obesity, two conditions associated with elevated risk for pancreatic cancer. Accordingly, our proposed work will first address the genetic and epigenetic differences that influence pancreatic cancer incidence and mortality in African American, Hispanic American, and Non-Hispanic White American patients. We hypothesize that in addition to the increased incidence of KRASG12V driver mutations observed in the African American population, there are other genetic and epigenetic differences that underlie the heightened malignancy of this disease in specific racial populations. These alterations may also influence other disease states that are associated with increased pancreatic cancer risk, such as diabetes, obesity, and chronic pancreatitis. Understanding these differences may identify new diagnostic and therapeutic targets that are more efficient at detecting and treating pancreatic cancer in these at-risk populations. To accomplish these goals, we will use a new three-dimensional, cell culture model system of pancreatic cancer progression called organoids. This culture system facilitates the rapid isolation and establishment of organoid lines from both normal and malignant human tissue. Upon isolation of patient-derived organoids from biopsies (fine needle aspirates), we will compare their genomes and transcriptomes both between racial and ethnic populations. Understanding the genetic and epigenetic counterpart to pancreatic carcinogenesis in tractable model systems will directly lead to the discovery of new biomarkers of pancreatic cancer such that early detection strategies can be developed. In addition, our findings may inform different treatment strategies and targets depending on the genomic and epigenomic landscape of the different patient populations. Given that these organoids are amenable to genetic manipulation through viral transduction or CRISPR/Cas mediated gene editing, these studies will enable iterative cycles of discovery and validation for future studies of genetic and epigenetic drivers of pancreatic cancer in under represented minorities.